Clinical trialPhase 3Lymphoma

Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial

Lancet · 20241500 patients (749 BrECADD, 751 eBEACOPP)

Borchmann P, Ferdinandus J, Schneider G, et al. Lancet. 2024. 404:341-352

Study type: Clinical trial
Study name: GHSG HD21
Phase: Phase 3
Design: Randomised (1:1), open-label, multicentre trial at 233 centres in 9 countries (German Hodgkin Study Group)
Sample size: 1500 patients (749 BrECADD, 751 eBEACOPP)
Source: Lancet · 2024
Trial registration: NCT02661503

In plain words

The eBEACOPP regimen was one of the strongest treatments for advanced Hodgkin lymphoma, but it had many side effects such as infertility and severe infections. In the new BrECADD regimen, several drugs with many side effects (such as bleomycin, vincristine and procarbazine) were removed and the targeted drug brentuximab vedotin was added. The result: fewer serious side effects and even better disease control; more than 94% of patients were free of relapse after 4 years. The number of treatment cycles is also decided by a PET scan after two cycles, so that patients who respond well receive a shorter treatment.

Key results

42% vs 59%

Treatment-related morbidity

Relative risk 0.72 (95% CI 0.65–0.80); p<0.0001

94.3% vs 90.9%

4-year progression-free survival

HR 0.66 (0.45–0.97); p=0.035 (superiority); median follow-up 48 months

98.6% vs 98.2%

4-year overall survival

Drugs in this study:Cyclophosphamide (Endoxan)Doxorubicin (Adriamycin)Etoposide

Dose and schedule cards

Escalated BEACOPP (eBEACOPP)

Unfavorable limited-stage Hodgkin lymphoma in patients aged 60 years or younger (2 cycles of eBEACOPP followed by 2 cycles of ABVD); treatment escalation after a positive interim PET on ABVDCycle length: Every 21 daysOn the page “Lymphoma” · Treatment regimens and dosing: Hodgkin lymphoma

Unfavorable limited-stage Hodgkin lymphoma in patients aged 60 years or younger (2 cycles of eBEACOPP followed by 2 cycles of ABVD); treatment escalation after a positive interim PET on ABVD

Drug	Dose	Route	Schedule
Etoposide	200 mg/m²	IV	Days 1–3
Doxorubicin	35 mg/m²	IV	Day 1
Cyclophosphamide	1250 mg/m²	IV	Day 1
Bleomycin	10 mg/m²	IV	Day 8
Vincristine	1.4 mg/m²	IV	Day 8
Procarbazine	100 mg/m²	Oral	Days 1–7
Prednisone	40 mg/m²	Oral	Days 1–14

Cycle length: Every 21 days
Duration: Unfavorable limited stage: 2 cycles followed by 2 cycles of ABVD; 30 Gy radiotherapy only if PET is positive at the end of chemotherapy

Doses from the abstract of the HD21 trial (eBEACOPP arm); its role in limited-stage disease from the EHA guideline. The accelerated version (BEACOPP-14) is given with granulocyte growth factor support. eBEACOPP carries a risk of permanent infertility, prolonged fatigue and myelodysplasia or acute leukaemia.

On the page “Lymphoma” · Treatment regimens and dosing: Hodgkin lymphoma

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1BrECADD (PET-guided after two cycles)

Four or six 21-day cycles (PET-negative after 2 cycles: 4 cycles; PET-positive: 6 cycles): brentuximab vedotin 1.8 mg/kg IV (over 30 minutes) on day 1, plus cyclophosphamide 1250 mg/m², doxorubicin 40 mg/m², etoposide (or etoposide phosphate) 150 mg/m², dacarbazine 250 mg/m² and dexamethasone 40 mg per cycle. All patients received primary prophylaxis with G-CSF. The administration days of the chemotherapy components are given in the full text of the paper.

2eBEACOPP (PET-guided after two cycles)

Four or six 21-day cycles: escalated doses of etoposide 200 mg/m² IV on days 1 to 3, doxorubicin 35 mg/m² IV on day 1 and cyclophosphamide 1250 mg/m² IV on day 1; and standard doses of bleomycin 10 mg/m² IV on day 8, vincristine 1.4 mg/m² IV on day 8, procarbazine 100 mg/m² orally on days 1 to 7 and prednisone 40 mg/m² orally on days 1 to 14.

Source of the regimen details: eBEACOPP doses from the abstract of the paper (Lancet 2024); BrECADD doses in HD21 from the EMA summary of product characteristics for ADCETRIS (section 5.1, Study HD21)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 60 years or younger with newly diagnosed advanced-stage classical Hodgkin lymphoma (Ann Arbor stage 3 or 4, or stage 2 with B symptoms and a large mediastinal mass and/or extranodal involvement). Median age 31 years.

Endpoints

Hierarchical co-primary endpoints: (1) better tolerability based on treatment-related morbidity (TRMB) and (2) non-inferior efficacy based on progression-free survival with an absolute margin of 6 percentage points; if non-inferiority was shown, a test for superiority.

Safety and side effects

Treatment-related morbidity (TRMB; mainly severe haematological and infectious adverse events) was significantly lower with BrECADD: 312 of 738 patients (42%) versus 430 of 732 patients (59%) with eBEACOPP.

Clinical significance and place in guidelines

PET-guided BrECADD has become one of the first-line standards in Europe for advanced classical Hodgkin lymphoma in adults aged 60 years or younger. In the USA, nivolumab-AVD (study S1826) is the prevailing approach; the two regimens have not yet been compared directly.

Limitations

The study was open-label and enrolled only patients aged 60 years or younger; most patients were White and European. The comparator is eBEACOPP, which is not the common standard in many countries (including the USA). Long-term data on infertility and second cancers are still being completed.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.